A new G-quadruplex-specific photosensitizer inducing genome instability in cancer cells by triggering oxidative DNA damage and impeding replication fork progression

• Published in: Nucleic acids research Vol. 51; no. 12; pp. 6264 - 6285
• Main Authors: Deiana, Marco, Andrés Castán, José María, Josse, Pierre, Kahsay, Abraha, Sánchez, Darío Puchán, Morice, Korentin, Gillet, Natacha, Ravindranath, Ranjitha, Patel, Ankit Kumar, Sengupta, Pallabi, Obi, Ikenna, Rodriguez-Marquez, Eva, Khrouz, Lhoussain, Dumont, Elise, Abad Galán, Laura, Allain, Magali, Walker, Bright, Ahn, Hyun Seo, Maury, Olivier, Blanchard, Philippe, Le Bahers, Tangui, Öhlund, Daniel, von Hofsten, Jonas, Monnereau, Cyrille, Cabanetos, Clément, Sabouri, Nasim
• Format: Journal Article
• Language: English
• Published: England Oxford University Press 07-07-2023
• Subjects: Animals; Cancer; Chemical Sciences; DNA - metabolism; DNA Damage; DNA Replication; G-Quadruplexes; Genome Integrity, Repair and; Genomic Instability; Life Sciences; Medicinal Chemistry; Neoplasms - genetics; Neoplasms - therapy; Oxidative Stress; Pharmaceutical sciences; Pharmacology; Photochemotherapy - methods; Photosensitizing Agents - pharmacology; Zebrafish - genetics; Zebrafish - metabolism
• ISSN: 0305-1048; 1362-4962; 1362-4962
• DOI: 10.1093/nar/gkad365

Abstract
Photodynamic therapy (PDT) ideally relies on the administration, selective accumulation and photoactivation of a photosensitizer (PS) into diseased tissues. In this context, we report a new heavy-atom-free fluorescent G-quadruplex (G4) DNA-binding PS, named DBI. We reveal by fluorescence microscopy that DBI preferentially localizes in intraluminal vesicles (ILVs), precursors of exosomes, which are key components of cancer cell proliferation. Moreover, purified exosomal DNA was recognized by a G4-specific antibody, thus highlighting the presence of such G4-forming sequences in the vesicles. Despite the absence of fluorescence signal from DBI in nuclei, light-irradiated DBI-treated cells generated reactive oxygen species (ROS), triggering a 3-fold increase of nuclear G4 foci, slowing fork progression and elevated levels of both DNA base damage, 8-oxoguanine, and double-stranded DNA breaks. Consequently, DBI was found to exert significant phototoxic effects (at nanomolar scale) toward cancer cell lines and tumor organoids. Furthermore, in vivo testing reveals that photoactivation of DBI induces not only G4 formation and DNA damage but also apoptosis in zebrafish, specifically in the area where DBI had accumulated. Collectively, this approach shows significant promise for image-guided PDT.
Graphical Abstract
Graphical Abstract
Photoactivation of a new heavy-atom free fluorescent G-quadruplex DNA-binding photosensitizer generates reactive oxygen species (ROS) that results in elevated levels of DNA damage och G-quadruplex formation.